tbuckley/cabot-search huggingface dataset:
A primary cell-based in vitro model of the human small intestine reveals host olfactomedin 4 induction in response to Salmonella Typhimurium infection
Authors: Thomas Däullary, Fabian Imdahl, Oliver Dietrich, Laura Hepp, Tobias Krammer, Christina Fey, Winfried Neuhaus, Marco Metzger, Jörg Vogel, Alexander J. Westermann, Antoine-Emmanuel Saliba, Daniela Zdzieblo
Journal: Gut Microbes (2023)

Infection research largely relies on classical cell culture or mouse models. Despite having delivered invaluable insights into host-pathogen interactions, both have limitations in translating mechanistic principles to human pathologies. Alternatives can be derived from modern Tissue Engineering approaches, allowing the reconstruction of functional tissue models in vitro. Here, we combined a biological extracellular matrix with primary tissue-derived enteroids to establish an in vitro model of the human small intestinal epithelium exhibiting in vivo-like characteristics. Using the foodborne pathogen Salmonella enterica serovar Typhimurium, we demonstrated the applicability of our model to enteric infection research in the human context. Infection assays coupled to spatio-temporal readouts recapitulated the established key steps of epithelial infection by this pathogen in our model. Besides, we detected the upregulation of olfactomedin 4 in infected cells, a hitherto unrecognized aspect of the host response to Salmonella infection. Together, this primary human small intestinal tissue model fills the gap between simplistic cell culture and animal models of infection, and shall prove valuable in uncovering human-specific features of host-pathogen interplay.
Expression and Therapeutic Targeting of TROP-2 in Treatment-Resistant Prostate Cancer
Authors: Jamie M. Sperger, Kyle T. Helzer, Charlotte N. Stahlfeld, Dawei Jiang, Anupama Singh, Katherine R. Kaufmann, David J. Niles, Erika Heninger, Nicholas R. Rydzewski, Liguo Wang, Liewei Wang, Rendong Yang, Yanan Ren, Jonathan W. Engle, Peng Huang, Christos E. Kyriakopoulos, Susan F. Slovin, Howard R. Soule, Shuang G. Zhao, Manish Kohli, Scott T. Tagawa, Weibo Cai, Scott M. Dehm, Joshua M. Lang
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Men with metastatic castration-resistant prostate cancer (mCRPC) frequently develop resistance to androgen receptor signaling inhibitor (ARSI) treatment; therefore, new therapies are needed. Trophoblastic cell-surface antigen (TROP-2) is a transmembrane protein identified in prostate cancer and overexpressed in multiple malignancies. TROP-2 is a therapeutic target for antibody–drug conjugates (ADC). Experimental Design: TROP-2 gene (TACSTD2) expression and markers of treatment resistance from prostate biopsies were analyzed using data from four previously curated cohorts of mCRPC (n = 634) and the PROMOTE study (dbGaP accession phs001141.v1.p1, n = 88). EPCAM or TROP-2–positive circulating tumor cells (CTC) were captured from peripheral blood for comparison of protein (n = 15) and gene expression signatures of treatment resistance (n = 40). We assessed the efficacy of TROP-2–targeting agents in a mouse xenograft model generated from prostate cancer cell lines. Results: We demonstrated that TACSTD2 is expressed in mCRPC from luminal and basal tumors but at lower levels in patients with neuroendocrine prostate cancer. Patients previously treated with ARSI showed no significant difference in TACSTD2 expression, whereas patients with detectable AR-V7 expression showed increased expression. We observed that TROP-2 can serve as a cell surface target for isolating CTCs, which may serve as a predictive biomarker for ADCs. We also demonstrated that prostate cancer cell line xenografts can be targeted specifically by labeled anti–TROP-2 agents in vivo. Conclusions: These results support further studies on TROP-2 as a therapeutic and diagnostic target for mCRPC.
Effectiveness of the <i>Family Heart Talk</i> Communication Tool in Improving Family Member Screening for Dilated Cardiomyopathy: Results of a Randomized Trial
Authors: Daniel D. Kinnamon, Elizabeth Jordan, Garrie J. Haas, Mark Hofmeyer, Evan Kransdorf, Gregory A. Ewald, Alanna A. Morris, Anjali Owens, Brian Lowes, Douglas Stoller, W.H. Wilson Tang, Sonia Garg, Barry H. Trachtenberg, Palak Shah, Salpy V. Pamboukian, Nancy K. Sweitzer, Matthew T. Wheeler, Jane E. Wilcox, Stuart Katz, Stephen Pan, Javier Jimenez, Keith D. Aaronson, Daniel P. Fishbein, Frank Smart, Jessica Wang, Stephen S. Gottlieb, Daniel P. Judge, Charles K. Moore, Jonathan O. Mead, Gordon S. Huggins, Hanyu Ni, Wylie Burke, Ray E. Hershberger
Journal: Circulation (2023)

Managing disease risk among first-degree relatives of probands diagnosed with a heritable disease is central to precision medicine. A critical component is often clinical screening, which is particularly important for conditions like dilated cardiomyopathy (DCM) that remain asymptomatic until severe disease develops. Nonetheless, probands are frequently ill-equipped to disseminate genetic risk information that motivates at-risk relatives to complete recommended clinical screening. An easily implemented remedy for this key issue has been elusive.
Keeping It Organized: Multicompartment Constructs to Mimic Tissue Heterogeneity
Authors: Alvaro Sanchez‐Rubio, Vineetha Jayawarna, Emily Maxwell, Matthew J. Dalby, Manuel Salmeron‐Sanchez
Journal: Advanced Healthcare Materials (2023)

Tissue engineering aims at replicating tissues and organs to develop applications in vivo and in vitro. In vivo, by engineering artificial constructs using functional materials and cells to provide both physiological form and function. In vitro, by engineering three-dimensional (3D) models to support drug discovery and enable understanding of fundamental biology. 3D culture constructs mimic cell-cell and cell-matrix interactions and use biomaterials seeking to increase the resemblance of engineered tissues with its in vivo homologues. Native tissues, however, include complex architectures, with compartmentalized regions of different properties containing different types of cells that can be captured by multicompartment constructs. Recent advances in fabrication technologies, such as micropatterning, microfluidics or 3D bioprinting, have enabled compartmentalized structures with defined compositions and properties that are essential in creating 3D cell-laden multiphasic complex architectures. This review focuses on advances in engineered multicompartment constructs that mimic tissue heterogeneity. It includes multiphasic 3D implantable scaffolds and in vitro models, including systems that incorporate different regions emulating in vivo tissues, highlighting the emergence and relevance of 3D bioprinting in the future of biological research and medicine.
Genome-Wide Splicing Quantitative Expression Locus Analysis Identifies Causal Risk Variants for Non–Small Cell Lung Cancer
Authors: Meng Jin, Bo Liu, Can Chen, Yongbiao Huang, Huixian Zhang, Bingliang Chen, Guoda Song, Dong Zhao, Limin Duan, Wei Liu, Haizhen Yang, Fang Yue, Peijun Liu, Xianglin Yuan, Qian Chu, Jianbo Tian, Ke Hu
Journal: Cancer Research (2023)

Abstract Alternative RNA splicing is an essential mechanism linking genetic variation to human diseases. While the signals from genome-wide association studies (GWAS) have been linked to expression quantitative trait loci (eQTL) in previous studies, further work is needed to better elucidate the relationship to other genetic regulatory mechanisms, such as splicing QTLs (sQTL). Here, we performed a genome-wide sQTL analysis to identify variants that might affect RNA splicing in 1,010 non–small cell lung cancer (NSCLC) samples from The Cancer Genome Atlas. The identified sQTLs were largely independent of eQTLs and were predominantly enriched in exonic regions, genetic regulatory elements, RNA-binding protein (RBP) binding sites, and known NSCLC risk loci. In addition, target genes affected by sQTLs (sGenes) were involved in multiple processes in cancer, including cell growth, apoptosis, metabolism, immune infiltration, and drug responses, and sGenes were frequently altered genetically in NSCLC. Systematic screening of sQTLs associated with NSCLC risk using GWAS data from 15,474 cases and 12,375 controls identified an sQTL variant rs156697-G allele that was significantly associated with an increased risk of NSCLC. The association between the rs156697-G variant and NSCLC risk was further validated in two additional large population cohorts. The risk variant promoted inclusion of GSTO2 alternative exon 5 and led to higher expression of the GSTO2 full-length isoform (GSTO2-V1) and lower expression of the truncated GSTO2 isoform (GSTO2-V2), which was induced by RBP quaking (QKI). Mechanistically, compared with GSTO2-V1, GSTO2-V2 inhibited NSCLC cells proliferation by increasing S-glutathionylation of AKT1 and thereby functionally blocking AKT1 phosphorylation and activation. Overall, this study provides a comprehensive view of splicing variants linked to NSCLC risk and provides a set of genetic targets with therapeutic potential. Significance: Analysis of sQTL reveals the role of genetically driven mRNA splicing alterations in NSCLC risk and elucidates that rs156697 variant impacts risk by altering GSTO2 splicing.
Perioperative Risk Assessment and Avoiding Overuse of Anesthesia Care for Routine Cataract Surgery—Reply
Authors: Dhivya Perumal, Sei J. Lee, Catherine L. Chen
Journal: JAMA Internal Medicine (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Effects of Racial Bias in Pulse Oximetry on Children and How to Address Algorithmic Bias in Clinical Medicine
Authors: Keyaria D. Gray, Hamsa L. Subramaniam, Erich S. Huang
Journal: JAMA Pediatrics (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Gender Disparity in National Institutes of Health Funding Among Surgeon-Scientists From 1995 to 2020
Authors: Mytien Nguyen, Luis Gonzalez, Sarwat I. Chaudhry, Nita Ahuja, Bohdan Pomahac, Ashley Newman, Ashley Cannon, Shenika A. Zarebski, Alan Dardik, Dowin Boatright
Journal: JAMA Network Open (2023)

Importance Surgical diseases account for approximately 30% of the global burden of disease. Gender diversity in biomedical research is critical to generate innovative patient-centered research in surgery. Objective To examine the distribution of biomedical research funding by the National Institutes of Health (NIH) among women and men surgeon-scientists during a 25-year period. Design, Setting, and Participants This cross-sectional study used publicly available data from the NIH RePORTER (Research Portfolio Online Reporting Tools: Expenditures and Results) database for research project grants awarded to women and men surgeon-scientists who were principal investigators between 1995 and 2020. Data were retrieved between January 20 and March 20, 2022. The representation of women surgeon-scientists among academic surgeons was compared with the representation of men surgeon-scientists over time. Main Outcomes and Measures Distribution of NIH funding to women and men surgeon-scientists was examined via 2 metrics: holding a large-dollar (ie, R01-equivalent) grant and being a super principal investigator (SPI) with $750 000 or more in total annual research funding. Statistical analysis was performed between April 1 and August 31, 2022. Results Between 1995 and 2020, 2078 principal investigator surgeons received funding from the NIH. The proportion of women academic surgeons who were surgeon-scientists remained unchanged during this same period (1995, 14 of 792 [1.8%] vs 2020, 92 of 3834 [2.4%]; P = .10). Compared with their men counterparts, women surgeon-scientists obtained their first NIH grant earlier in their career (mean [SD] years after first faculty appointment, 8.8 [6.2] vs 10.8 [7.9] years; P &amp;amp;lt; .001) and were as likely to obtain large-dollar grants (aRR, 0.99 [95% CI, 0.95-1.03]) during the period 2016 to 2020. Despite this success, women surgeon-scientists remained significantly underrepresented among SPIs and were 25% less likely to be an SPI (aRR, 0.75 [95% CI, 0.60-0.95] during the period 2016 to 2020). Conclusions and Relevance The findings of this cross-sectional study of NIH-funded surgeons suggest that women surgeons remained underrepresented among surgeon-scientists over a 25-year period despite early career success in receiving NIH funding. This is concerning and warrants further investigation to increase the distribution of NIH funding among women surgeon-scientists.
Cancer-Associated Fibroblast–Derived miR-146a-5p Generates a Niche That Promotes Bladder Cancer Stemness and Chemoresistance
Authors: Junlong Zhuang, Lan Shen, Meiqian Li, Jingya Sun, Jiange Hao, Jiaxuan Li, Zhen Zhu, Shuning Ge, Dianzheng Zhang, Hongqian Guo, Ruimin Huang, Jun Yan
Journal: Cancer Research (2023)

Abstract Cancer stem-like cells (CSC) play pivotal roles in both chemoresistance and recurrence of many cancer types, including urothelial bladder cancer (UBC). In addition to intrinsic signaling pathways, extracellular cues from the tumor microenvironment (TME) are indispensable for the maintenance of CSCs. To better understand the mechanisms involved in TME-mediated generation and support of UBC CSCs, we focused on the role of cancer-associated fibroblasts (CAF) in this study. Overexpression of miR-146a-5p in CAFs promoted CAF-to-UBC cell interactions, cancer stemness, and chemoresistance to treatment with gemcitabine and cisplatin. Mechanistically, miR-146–5p upregulated SVEP1 in CAFs by enhancing the recruitment of transcriptional factor YY1. Meanwhile, by targeting the 3′UTR of mRNAs of ARID1A and PRKAA2 (also known as AMPKα2) in UBC cells, CAF-secreted miR-146a-5p promoted cancer stemness and chemoresistance. Downregulation of ARID1A resulted in the inhibition of SOCS1 and subsequent STAT3 activation, and downregulated PRKAA2 led to the activation of mTOR signaling. Elevated levels of exosomal miR-146a-5p in the serum of patients with UBC were correlated with both tumor stage and relapse risk. These findings altogether indicate that CAF-derived miR-146a-5p can promote stemness and enhance chemoresistance in UBC. Exosomal miR-146a-5p may be a biomarker of UBC recurrence and a potential therapeutic target. Significance: The tumor–stromal cross-talk mediated by cancer-associated fibroblast–derived miR-146a-5p fosters cancer stem cell niche formation and cancer stemness to drive chemoresistance in urothelial bladder cancer.
Evaluating the Accuracy of Pulse Oximetry in Children According to Race
Authors: Halley Ruppel, Spandana Makeneni, Jennifer A. Faerber, Meghan B. Lane-Fall, Elizabeth E. Foglia, Michael L. O’Byrne, Christopher P. Bonafide
Journal: JAMA Pediatrics (2023)

This cross-sectional study investigates the association between race and pulse oximeter accuracy in children in the US.
Clonal hematopoiesis of indeterminate potential and clonal cytopenias of undetermined significance: 2023 update on clinical associations and management recommendations
Authors: Abhishek A. Mangaonkar, Mrinal M. Patnaik
Journal: American Journal of Hematology (2023)

Abstract Condition Overview Clonal hematopoiesis (CH) refers to age‐associated expansion of somatic variants in hematopoietic stem and progenitor cells (HSPC). Diagnosis CH of indeterminate potential (CHIP) is operationally defined as pathogenic variants in HSPCs at a variant allele frequency ≥2%. Clinical Associations CH is associated with increased occurrence of several hematological conditions such as cytopenias (also called clonal cytopenia of undetermined significance), hematological (predominantly myeloid but also lymphoid) neoplasms, cytosis (including monocytosis), and non‐hematological conditions such as atherosclerotic cardiovascular and cerebrovascular disease, ischemic congestive heart failure, venous thromboembolism, type 2 diabetes mellitus, chronic obstructive pulmonary disease, osteoporosis, gout, with a potential protective effect in Alzheimer's disease (AD). Management Recommendations As of now, there is limited prospective data for CH testing; however, CH detection is becoming increasingly prevalent due to ubiquitous use of somatic and germline NGS testing. This in addition to data suggesting that therapy related myeloid neoplasm (tMN) in many cases is preceded by the detection of CH clones, has led to the establishment of CH clinics at several institutions. At our institution, on a research basis, we currently recommend testing for CH for individuals with persistent (≥4 months) unexplained cytopenias, in patients with malignancies prior to adjuvant cytotoxic chemotherapy and/or radiation or radionuclide therapy, screening prior to autologous hematopoietic stem cell transplantation and chimeric antigen receptor T cell (CAR‐T) therapy and to assess as to whether or not, potential germline mosaic variants actually represent CH.
Sequential Dual‐Biofactor Release from the Scaffold of Mesoporous HA Microspheres and PLGA Matrix for Boosting Endogenous Bone Regeneration
Authors: Jiawei Wei, Xue Xia, Shiqi Xiao, Shue Jin, Qin Zou, Yi Zuo, Yubao Li, Jidong Li
Journal: Advanced Healthcare Materials (2023)

Abstract The combined design of scaffold structure and multi‐biological factors is a prominent strategy to promote bone regeneration. Herein, a composite scaffold of mesoporous hydroxyapatite (HA) microspheres loaded with the bone morphogenetic protein‐2 (BMP‐2) and a poly(DL‐lactic‐co‐glycolic acid) (PLGA) matrix is constructed by 3D printing. Furthermore, the chemokine stromal cell‐derived factor‐1 α (SDF‐1 α ) is adsorbed on a scaffold surface to achieve the sequential release of the dual‐biofactors. The results indicate that the rapid release of SDF‐1 α chemokine on the scaffold surface effectively recruits bone marrow‐derived mesenchymal stem cells (BMSCs) to the target defect area, whereas the long‐term sustained release of BMP‐2 from the HA microspheres in the degradable PLGA matrix successfully triggers the osteogenic differentiation in the recruited BMSCs, significantly promoting bone regeneration and reconstruction. In addition, these structures/biofactors specially combining scaffold exhibit significantly better biological performance than that of other combined scaffolds, including the bare HA/PLGA scaffold, the scaffold loaded with SDF‐1 α or BMP‐2 biofactor alone, and the scaffold with surface SDF‐1 α and BMP‐2 dual‐biofactors. The utilization of mesoporous HA, the assembly method, and sequential release of the two biofactors in the 3D printed composite scaffold present a new method for future design of high‐performance bone repairing scaffolds.
DAB2IP Is a Bifunctional Tumor Suppressor That Regulates Wild-Type RAS and Inflammatory Cascades in KRAS Mutant Colon Cancer
Authors: Abigail L. Miller, Naiara Perurena, Alycia Gardner, Toshinori Hinoue, Patrick Loi, Peter W. Laird, Karen Cichowski
Journal: Cancer Research (2023)

Abstract The DAB2IP tumor suppressor encodes a RAS GTPase-activating protein. Accordingly, DAB2IP has been shown to be mutated or suppressed in tumor types that typically lack RAS mutations. However, here we report that DAB2IP is mutated or selectively silenced in the vast majority of KRAS and BRAF mutant colorectal cancers. In this setting, DAB2IP loss promoted tumor development by activating wild-type H- and N-RAS proteins, which was surprisingly required to achieve robust activation of RAS effector pathways in KRAS-mutant tumors. DAB2IP loss also triggered production of inflammatory mediators and the recruitment of protumorigenic macrophages in vivo. Importantly, tumor growth was suppressed by depleting macrophages or inhibiting cytokine/inflammatory mediator expression with a JAK/TBK1 inhibitor. In human tumors, DAB2IP was lost at early stages of tumor development, and its depletion was associated with an enrichment of macrophage and inflammatory signatures. Together, these findings demonstrate that DAB2IP restrains the activation of the RAS pathway and inflammatory cascades in the colon and that its loss represents a common and unappreciated mechanism for amplifying these two critical oncogenic signals in colorectal cancer. Significance: DAB2IP is lost in early-stage tumors, which amplifies RAS signaling, triggers inflammatory mediators, and recruits macrophages in KRAS-mutant colon cancers.
Emerging targets for therapy in ALD: Lessons from NASH
Authors: Ashwani K. Singal, Vijay H. Shah, Harmeet Malhi
Journal: Hepatology (2023)

Alcohol-associated liver disease due to harmful alcohol use and NAFLD associated with metabolic syndrome are the 2 most common liver diseases worldwide. Control of respective risk factors is the cornerstone in the long-term management of these diseases. Furthermore, there are no effective therapies. Both diseases are characterized by metabolic derangements; thus, the focus of this review was to broaden our understanding of metabolic targets investigated in NAFLD, and how these can be applied to alcohol-associated liver disease. Conserved pathogenic pathways such as dysregulated lipid metabolism, cell death pathways including apoptosis and activation of innate immune cells, and stellate cells mediate both alcohol and NAFLDs, resulting in histological abnormalities of steatosis, inflammation, fibrosis, and cirrhosis. However, pathways such as gut microbiome changes, glucose metabolism and insulin resistance, inflammatory signaling, and microRNA abnormalities are distinct in these 2 diseases. In this review article, we describe conserved and distinct pathogenic pathways highlighting therapeutic targets that may be of potential in both diseases and those that are unique to each disease.